CCR7 REGULATION OF IMMUNE AND NON-IMMUNE CELL ADHESION/MIGRATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Following pathogen invasion, immune cells migrate to sites of chemokine production. C-C chemokine receptor 7, is a G protein-coupled receptor that controls lymphocyte migration to lymph nodes by regulating adhesion of primarily beta 1 and beta 2 integrins (heterodimeric transmembrane, adhesion proteins). Our initial studies confirmed CCR7 regulated beta 2 integrin adhesion of T-lymphocytes to LFA-1. Our novel findings revealed CCR7 differentially regulates beta 1 integrin adhesion and migration on fibronectin and VCAM. We have also observed that CCR7 regulates beta1 integrin adhesion in breast cancer cells. To extend our studies we hypothesized that CCR7 targets lymph node metastasis and mediates immune surveillance during metastasis. We are testing this hypothesis by expressing CCR7, in three mouse models of breast cancer ; (1) FVB model with PyVMT cells- which metastasize only to lung- to determine if CCR7 can alter targeting of metastases. (2) Balb/c mice with 4T1 cells- which metastasize to lung, liver, and bone to determine whether early expression of CCR7 and/or early arrival at lymph nodes can trigger a protective immune response. (3) Balb/c mice with 67NR cells- which form mammary tumors but fail to metastasize, to determine if CCR7 can induce metastases. To measure CCR7 in primary breast cancer cell isolates for our mouse studies, we are currently developing an RT-PCR assay and sequencing CCR7 in the established breast cancer cell lines: MDA-MB-231, MCF10A and MCF7. Overall, these studies will provide us with a better understanding of the role of CCR7 in the immune response and breast cancer progression to metastasis.